Quinoline derivative-containing pharmaceutical composition

ABSTRACT

A pharmaceutical composition comprising a compound represented by the formula (I) or pharmaceutically acceptable salt thereof or solvate thereof, and a basic substance is excellent in dissolution, is stable even after a long term storage, and is useful as a preventive or therapeutic agent against a tumor: 
     
       
         
         
             
             
         
       
     
     wherein, R 1  is a hydrogen atom, a C 1-6  alkyl group or a C 3-8  cycloalkyl group; and R 2  is a hydrogen atom or a methoxy group.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition comprisinga quinoline derivative, useful as a medicament. More specifically, thepresent invention relates to a pharmaceutical composition improved indissolution of a quinoline derivative or a pharmaceutically acceptablesalt thereof or a solvate thereof.

BACKGROUND ART

A quinoline derivative represented by the formula (I) or apharmaceutically acceptable salt thereof or a solvate thereof(hereinafter referred to as quinoline derivative (I)) has been known tohave a potent angiogenesis inhibitory effect (Patent Literature 1) and ac-Kit kinase inhibitory effect (Patent Literature 2) and to be useful asa preventive or therapeutic agent against various tumors such as thyroidcancer, lung cancer, melanoma and pancreatic cancer, and as anmetastatic inhibitor against these tumors:

wherein, R¹ is a hydrogen atom, a C₁₋₆ alkyl group or a C₃₋₈ cycloalkylgroup; and R² is a hydrogen atom or a methoxy group.

However, the quinoline derivative (I) has been found to degrade underhumidifying and warming storage conditions when formulated into apharmaceutical composition. In addition, when the pharmaceuticalcomposition absorbs moisture, dissolution of the quinoline derivative(I) from the pharmaceutical composition that is an active ingredient maydelay because of gelation on the surface of the composition. In order toovercome these problems, a pharmaceutical composition which includes thequinoline derivative (I), (1) a compound, a 5% (w/w) aqueous solution orsuspension of which has a pH of 8 or more, and/or (2) silicic acid, saltthereof or solvate thereof has been developed (Patent Literature 3).

CITATION LIST Patent Literature

Patent Literature 1: WO 2002/32872

Patent Literature 2: WO 2004/080462

Patent Literature 3: WO 2006/030826

SUMMARY OF INVENTION Technical Problem

However, development of a pharmaceutical composition further excellentin the dissolution of the quinoline derivative (I) has been desired.Thus, the present invention is aimed at providing a pharmaceuticalcomposition that is excellent in dissolution of the quinoline derivative(I) that is maintained even after long term storage.

Solution to Problem

The present inventors have intensively studied in order to solve theproblems above and surprisingly have discovered the configuration belowcould solve the problems and have completed the present invention.

Specifically, the present invention provides the following <1> to <12>.

-   [1] A pharmaceutical composition comprising:

(1) a compound represented by the formula (I) or pharmaceuticallyacceptable salt thereof or solvate thereof:

wherein R¹ is a hydrogen atom, a C₁₋₆ alkyl group or a C₃₋₈ cycloalkylgroup; and R² represents a hydrogen atom or a methoxy group; and

(2) a basic substance.

-   [2] The composition according to [1], wherein the basic substance is    a carbonate.-   [3] The composition according to [2], wherein the salt is an    alkaline earth metal salt.-   [4] The composition according to [3], wherein the alkaline earth    metal salt is a magnesium salt or a calcium salt.-   [5] The composition according to any one of [1] to [4], further    comprising a disintegrating agent.-   [6] The composition according to [5], wherein the disintegrating    agent is carmellose sodium, carmellose calcium, carboxymethyl starch    sodium, croscarmellose sodium, low-substituted    hydroxypropylcellulose or crospovidone.-   [7] The composition according to any one of [1] to [6], wherein R¹    is a hydrogen atom, a methyl group, an ethyl group, an n-propyl    group or a cyclopropyl group.-   [8] The composition according to any one of [1] to [7], wherein R¹    is a cyclopropyl group.-   [9] The composition according to any one of [1] to [8], wherein R²    is a hydrogen atom, a methoxy group or an ethoxy group.-   [10] The composition according to any one of [1] to [9], wherein R²    is a hydrogen atom.-   [11] The composition according to any one of [1] to [10], wherein    the pharmaceutically acceptable salt is hydrochloride, hydrobromide,    p-toluenesulfonate, sulfate, methanesulfonate or ethanesulfonate.-   [12] The composition according to any one of [1] to [11], wherein    the compound represented by the formula (I) is    4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide    methanesulfonate.

Advantageous Effects of Invention

The pharmaceutical composition of the present invention is excellent indissolution of the quinoline derivative (I), which is a principal agent,and is also excellent in absorption into a living body. Thepharmaceutical composition is also a pharmaceutical composition that ismaintained even after long term storage.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the dissolution profiles of the compound A from thepharmaceutical compositions obtained in Examples 4 to 6 and ComparativeExample 1.

FIG. 2 shows the dissolution profiles of the compound A from thepharmaceutical compositions obtained in Examples 7 to 9 and ComparativeExample 2.

FIG. 3 shows the dissolution patterns of the compound A from thepharmaceutical compositions obtained in Examples 10 to 12 andComparative Example 3.

FIG. 4 shows the dissolution profiles of the compound A from thepharmaceutical compositions obtained in Examples 13 to 15 andComparative Example 4.

FIG. 5 shows the dissolution profiles of the compound A from thepharmaceutical compositions obtained in Examples 16 to 17 andComparative Example 5.

FIG. 6 shows the dissolution profiles of the compound A from thepharmaceutical compositions obtained in Example 18 and ComparativeExamples 7 to 8.

FIG. 7 shows the dissolution profiles of the compound A from thepharmaceutical compositions obtained in Example 19 and ComparativeExamples 9 to 10.

DESCRIPTION OF EMBODIMENTS

The pharmaceutical composition of the present invention means acomposition comprising the quinoline derivative (I) and a basicsubstance as essential ingredients. A mixing ratio of the quinolinederivative (I) and the basic substance is, but is not limited to,normally 1:0.5 to 50, preferably 1:1 to 25, further preferably 1:2 to12.5.

In addition, a mixing rate of the quinoline derivative (I) with respectto the total weight of the pharmaceutical composition (excluding acapsule shell) is normally 0.25 to 50 weight %, preferably 0.5 to 25weight %, further preferably 1 to 12.5 weight %.

A mixing rate of the basic substance with respect to the total weight ofthe pharmaceutical composition is normally 1 to 60 weight %, preferably5 to 50 weight %, further preferably 10 to 40 weight %. At least onebasic substance of the present invention may be included in thepharmaceutical composition, or two or more basic substances may also beincluded.

A dosage form of the pharmaceutical composition specifically means asolid preparation such as granules, fine granules, tablets or capsulesand so on. It is preferably fine granules, granules or capsules filledwith fine granules or granules.

The quinoline derivative (I) is a compound disclosed in WO 2002/32872. Apreferable quinoline derivative (I) is a quinoline derivative orpharmacologically acceptable salt thereof or solvate thereof selectedfrom the group consisting of4-(3-fluoro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-hydroxyethoxy)-6-quinolinecarboxamide,4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((2S)-2,3-dihydroxypropyl)oxy-6-quinolinecarboxamide,4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide,4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-ethoxyethoxy)-6-quinolinecarboxamide,4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,N-(2-fluoro-4-[(6-carbamoyl-7-methoxy-4-quinolyl)oxy]phenyl)-N′-cyclopropylurea,N6-(2-hydroxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide,4-(3-chloro-4-(1-propylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,4-(3-chloro-4-(cis-2-fluoro-cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamideandN6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide.

A more preferable quinoline derivative (I) is a quinoline derivative orpharmacologically acceptable salt thereof or solvate thereof selectedfrom the group consisting of4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamideandN6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide.

A particularly preferable quinoline derivative (I) is4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamideor pharmacologically acceptable salt thereof or solvate thereof.

The pharmaceutically acceptable salt of the present invention meanshydrochloride, hydrobromide, p-toluenesulfonate, sulfate,methanesulfonate or ethanesulfonate. It is preferably themethanesulfonate.

The solvate of the present invention means hydrate, dimethyl sulfoxidesolvate or acetic acid solvate.

The quinoline derivative (I) is preferably a crystal of a salt of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,or a solvate thereof disclosed in WO 2005/063713. A particularlypreferred quinoline derivative (I) is the C Form crystal of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamidemethanesulfonate.

The quinoline derivative (I) is useful as a preventive or therapeuticagent against various tumors and as a metastasis inhibitor againsttumors. Examples of the tumors against which the quinoline derivative(I) is effective include thyroid cancer, non-small-cell lung cancer,melanoma, laryngopharyngeal cancer, esophageal cancer, gastric cancer,colorectal cancer, hepatocellular carcinoma, renal cell carcinoma,pancreatic cancer, bladder cancer, breast cancer, uterine cancer,ovarian cancer, prostate cancer, testicular cancer, gastrointestinalstromal tumor, sarcoma, osteogenic sarcoma, angioma, malignant lymphoma,myeloid leukemia, neuroma and neuroglioma.

The basic substance of the present invention means a basic inorganicsalt. Such basic inorganic salts include beryllium carbonate, magnesiumcarbonate, calcium carbonate, strontium carbonate, barium carbonate,potassium carbonate, calcium hydrogenphosphate and titanium oxide. It ispreferably an alkaline earth metal salt of carbonic acid, furtherpreferably magnesium carbonate or calcium carbonate.

It is also acceptable to further include a disintegrating agent in thepharmaceutical composition of the present invention. Such adisintegrating agent include corn starch, partially pregelatinizedstarch, hydroxypropyl starch, carmellose, carmellose sodium, carmellosecalcium, carboxymethyl starch sodium, croscarmellose sodium,low-substituted hydroxypropylcellulose and crospovidone. It ispreferably the croscarmellose sodium, the low-substitutedhydroxypropylcellulose or the crospovidone.

The pharmaceutical composition of the present invention may be preparedby a known method such as a method described in the General Rules forPreparations in the Japanese Pharmacopoeia Fifteenth Edition.

For example, in the case of the granule, it is possible to add anexcipient, a binder, a disintegrating agent, a solvent, or the like tothe quinoline derivative (I) as needed, to perform agitationgranulation, extruding granulation, tumbling granulation, fluidized-bedgranulation, spray granulation, or the like, and to prepare it. It isalso acceptable to be coated with an atomizing agent containing thequinoline derivative (I) and an additive such as corn starch,microcrystalline cellulose, hydroxypropylcellulose, methylcellulose orpolyvinylpyrrolidone while spraying water or a solution of a binder suchas saccharose, hydroxypropylcellulose or hydroxypropylmethylcellulose ona core material such as a purified sucrose spherical granule, alactose/crystalline cellulose spherical granule, a saccharose/starchspherical granule or a granular crystalline cellulose. It is alsoacceptable to perform sizing and milling as needed.

It is also possible to further, as needed, add an excipient, a binder, adisintegrating agent, a lubricant, an anti-oxidizing agent, a corrigent,a coloring agent, a flavoring agent, or the like to the granule preparedin this way and to compress it to be a tablet. A required excipient maybe added to the quinoline derivative (I) to directly compress themixture into a tablet. It is also possible to fill a capsule with thequinoline derivative (I) added/mixed with an excipient such as lactose,saccharose, glucose, starch, microcrystalline cellulose, powderedglycyrrhiza, mannitol, calcium phosphate or calcium sulfate, or with thegranule.

Examples of the excipient include lactose, saccharose, glucose,fructose, starch, potato starch, corn starch, wheat starch, rice starch,crystalline cellulose, microcrystalline cellulose, powdered glycyrrhiza,mannitol, erythritol, maltitol, sorbitol, trehalose, silicic anhydride,calcium silicate, sodium hydrogencarbonate, calcium phosphate, anhydrouscalcium phosphate and calcium sulfate.

Examples of the binder include gelatin, starch, gum arabic, tragacanth,carboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose,partially pregelatinized starch, pregelatinized starch, polyvinylalcohol, sodium arginine, pullulan and glycerin.

Examples of the disintegrating agent include corn starch, partiallypregelatinized starch, hydroxypropyl starch, carmellose, carmellosesodium, carmellose calcium, carboxymethyl starch sodium, croscarmellosesodium, low-substituted hydroxypropylcellulose and crospovidone.

Examples of the lubricant include magnesium stearate, stearic acid,calcium stearate, sodium stearyl fumarate, talc and macrogol.

Examples of the anti-oxidizing agent include sodium ascorbate,L-cysteine, sodium sulfite, tocopherol and soybean lecithin.

Examples of the corrigent include citric acid, ascorbic acid, tartaricacid, malic acid, aspartame, acesulfame potassium, thaumatin, saccharinsodium, dipotassium glycyrrhizinate, sodium glutamate, sodium5′-inosinate and sodium 5′-guanylate.

Examples of the coloring agent include titanium oxide, iron sesquioxide,iron sesquioxide yellow, cochineal, carmine, riboflavin, food yellow No.5 and food blue No. 2.

Examples of the flavoring agent include lemon oil, orange oil, menthol,peppermint oil, borneol and vanilla flavor.

EXAMPLES

The present invention will be described in more detail below withreference to Examples, but is not limited to the Examples.

Examples 1 to 3

Wet granulation was performed with purified water as a solvent using ahigh-shear granulator (apparatus name: FM-VG-10, manufactured by PowrexCorporation) with the C form crystal of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamidemethanesulfonate (hereinafter referred to as compound A), D-mannitol(trade name: Mannitol, Merck), precipitated calcium carbonate (tradename: Whiton F, Shiraishi Calcium), hydroxypropylcellulose (HPC-L,Nippon Soda), low-substituted hydroxypropylcellulose (trade name: L-HPC(LH-21), Shin-Etsu Chemical) and microcrystalline cellulose (trade name:Ceolus PH-101, Asahi Kasei Chemicals) according to the formulationproportions in Table 1. The granules of which a moisture content wasreduced to be less than 2% by further drying were sized using a screenmill (apparatus name: Power Mill P-04S, manufactured by Showa Giken KK)so that their granule diameters were less than 1 mm. Then,microcrystalline cellulose (trade name: Ceolus PH-102, Asahi KaseiChemicals) and talc (trade name: Hi-Filler 17, Iwai Chemicals Company)were added to the sized granules according to the formulationproportions in Table 1, and the mixture was thoroughly mixed using adiffusion (tumbler-type) mixer (trade name: 10L/20L Exchange-typeTumbler Mixer, manufactured by Toyo Packing Corporation). Hard capsulessize #4 were filled with 100 mg of the resultant granules to preparecapsules containing the compound A.

TABLE 1 Ex. 1 Ex. 2 Ex. 3 Compound A 1.25 5 12.5 Precipitated calciumcarbonate 33 33 33 D-Mannitol 19.75 16 8.5 Hydroxypropylcellulose 3 3 3Low-substituted hydroxypropylcellulose 25 25 25 Microcrystallinecellulose (PH-101) 10 10 10 Microcrystalline cellulose (PH-102) 5 5 5Talc 3 3 3 Total 100 100 100 Unit: weight %

Examples 4 to 9, Comparative Examples 1 to 2

The compound A, precipitated calcium carbonate, low-substitutedhydroxypropylcellulose, D-mannitol and talc were thoroughly mixed usinga mortar and a pestle according to the formulation proportions in Table2 and Table 3. Hard capsules size #3 were filled with 100 mg of theresultant mixtures to prepare capsules in Examples 4 to 9. Capsules inComparative Examples 1 to 2, which contained no precipitated calciumcarbonate, were also prepared by the same method.

TABLE 2 Com. Ex. 1 Ex. 4 Ex. 5 Ex. 6 Compound A 5 5 5 5 Precipitatedcalcium carbonate 0 5 10 20 Low-substituted hydroxypropyl- 30 25 20 10cellulose D-Mannitol 62 62 62 62 Talc 3 3 3 3 Total 100 100 100 100Unit: weight %

TABLE 3 Com. Ex. 2 Ex. 7 Ex. 8 Ex. 9 Compound A 20 20 20 20 Precipitatedcalcium carbonate 0 5 10 20 Low-substituted hydroxypropyl- 30 25 20 10cellulose D-Mannitol 47 47 47 47 Talc 3 3 3 3 Total 100 100 100 100Unit: weight %

Test Example 1

The dissolutions of the compound A in the capsules in Examples 4 to 9and Comparative Examples 1 to 2 were examined according to theDissolution Test (the Paddle method, test medium: JP1 solution)described in the Japanese Pharmacopoeia Fifteenth Edition. As a result,the dissolutions of the compound A in the capsules in ComparativeExamples 1 to 2, in which no calcium carbonate was mixed, wereinsufficient. In contrast, the dissolutions of the compound A in thecapsules in Examples 4 to 9, in which calcium carbonate was mixed, weregood (FIG. 1 and FIG. 2).

Examples 10 to 15, Comparative Examples 3 to 4

The compound A, magnesium carbonate (Kyowa Chemical Industry),low-substituted hydroxypropylcellulose, D-mannitol and talc werethoroughly mixed using a mortar and a pestle according to theformulation proportions in Table 4 and Table 5. Hard capsules size #3were filled with 100 mg of the resultant mixtures to prepare capsules inExamples 10 to 15. Capsules in Comparative Examples 3 to 4, whichcontained no magnesium carbonate, were also prepared by the same method.

TABLE 4 Com. Ex. 3 Ex. 10 Ex. 11 Ex. 12 Compound A 5 5 5 5 Magnesiumcarbonate 0 5 10 20 Low-substituted hydroxypropyl- 30 25 20 10 celluloseD-Mannitol 62 62 62 62 Talc 3 3 3 3 Total 100 100 100 100 Unit: weight %

TABLE 5 Com. Ex. 4 Ex. 13 Ex. 14 Ex. 15 Compound A 20 20 20 20 Magnesiumcarbonate 0 5 10 20 Low-substituted hydroxypropyl- 30 25 20 10 celluloseD-Mannitol 47 47 47 47 Talc 3 3 3 3 Total 100 100 100 100 Unit: weight %

Test Example 2

The dissolutions of the compound A in the capsules in Examples 10 to 15and Comparative Examples 3 to 4 were examined by the same method as inTest Example 1. The dissolutions of the compound A in the capsules inComparative Examples 3 to 4, in which no magnesium carbonate was mixed,were insufficient. In contrast, the dissolutions of the compound A inthe capsules in Examples 10 to 15, in which the magnesium carbonate wasmixed, were good (FIG. 3 and FIG. 4).

Examples 16 to 17, Comparative Examples 5 to 6

Purified water was added to the compound A, precipitated calciumcarbonate or magnesium carbonate, hydroxypropylcellulose andcroscarmellose sodium (trade name: Ac-Di-Sol, Asahi Kasei Chemicals) toperform granulation using a mortar and a pestle, followed by sizing ofthe dried granules so that their granule diameters were less than 1 mm.Then, microcrystalline cellulose (trade name: Ceolus PH-102, Asahi KaseiChemicals), low-substituted hydroxypropylcellulose and talc (trade name:Hi-Filler 17, Iwai Chemicals Company) were added to the sized granulesaccording to the formulation proportions in Table 6, and the mixture wasmixed thoroughly. Hard capsules size #4 were filled with 100 mg of theresultant mixtures to prepare capsules in Examples 16 to 17. Capsules inComparative Examples 5 to 6, which contained neither precipitatedcalcium carbonate nor magnesium carbonate but contained mannitol or talcas a substitute, were also similarly prepared according to theformulation proportions in Table 7.

TABLE 6 Ex. 16 Ex. 17 Compound A 10 10 Precipitated calcium carbonate 150 Magnesium carbonate 0 15 Hydroxypropylcellulose 2 2 Croscarmellosesodium 10 10 Low-substituted hydroxypropylcellulose 20 20Microcrystalline cellulose (PH-102) 41 41 Talc 2 2 Total 100 100 Unit:weight %

TABLE 7 Com. Ex. 5 Com. Ex. 6 Compound A 10 10 Mannitol 15 0 Talc 0 15Hydroxypropylcellulose 2 2 Croscarmellose sodium 10 10 Low-substitutedhydroxypropylcellulose 20 20 Microcrystalline cellulose (PH-102) 41 41Talc 2 2 Total 100 100 Unit: weight %

Test Example 3

The dissolutions of the compound A in the capsules in Examples 16 to 17and Comparative Example 5 were examined by the same method as in TestExample 1. The dissolution of the compound A in the capsule inComparative Example 5, in which neither calcium carbonate nor magnesiumcarbonate was mixed, was insufficient. In contrast, the dissolutions ofthe compound A in the capsules in Examples 16 to 17, in which calciumcarbonate or magnesium carbonate was mixed, were good (FIG. 5).

Test Example 4

The capsules in Examples 16 to 17 and Comparative Example 6 were storedfor 1 week in an open system under an environment at a temperature of60° C. and a relative humidity of 75%, followed by determining theproduction of the degradants with high-performance liquidchromatography. In the capsule formulation in Comparative Example 6, inwhich neither calcium carbonate nor magnesium carbonate was mixed, anamount of the degradants was increased. In contrast, in the capsules inExamples 16 to 17, in which calcium carbonate or magnesium carbonate wasmixed, no increase in amount of the degradants was observed (Table 8).

TABLE 8 Degradants (%) Quantitated compound A(%) Compound A (Initial)1.61% 98.38% Com. Ex. 6 1.92% 98.08% Ex. 16 1.50% 98.50% Ex. 17 1.57%98.44%

Examples 18 to 19, Comparative Examples 7 to 10

The respective ingredients were mixed according to the formulations ofTables 9 and 10 by the same method as in Examples 4 to 9 and ComparativeExamples 1 to 2. Hard capsules size #3 were filled with 100 mg of theresultant mixtures to prepare capsules in Examples 18 to 19 andComparative Examples 7 to 10.

TABLE 9 Com. Com. Ex. 18 Ex. 7 Ex. 8 Compound A 20 20 20 Precipitatedcalcium carbonate 10 0 0 Calcium oxide 0 10 0 Calcium hydroxide 0 0 10Low-substituted hydroxypropyl- 20 20 20 cellulose D-Mannitol 47 47 47Talc 3 3 3 Total 100 100 100 Unit: weight %

TABLE 10 Com. Com. Ex. 19 Ex. 9 Ex. 10 Compound A 20 20 20 Magnesiumcarbonate 10 0 0 Magnesium oxide 0 10 0 Magnesium hydroxide 0 0 10Low-substituted hydroxypropyl- 20 20 20 cellulose D-Mannitol 47 47 47Talc 3 3 3 Total 100 100 100 Unit: weight %

Test Example 5

The dissolutions of the compound A in the capsules in Examples 18 to 19and Comparative Examples 7 to 10 were examined by the same method as inTest Example 1. As a result, the dissolutions of the compound A in thecapsules in Comparative Examples 7 to 10, in which calcium oxide,calcium hydroxide, magnesium oxide or magnesium hydroxide was mixed,were insufficient. In contrast, the dissolutions of the compound A inthe capsules in Examples 18 to 19, in which calcium carbonate ormagnesium carbonate was mixed, were good (FIG. 6 and FIG. 7).

INDUSTRIAL APPLICABILITY

The pharmaceutical composition of the present invention is excellent indissolution of the quinoline derivative and also in stability, and istherefore useful as a medicament for prevention or treatment of a tumor.

1-12. (canceled)
 13. A pharmaceutical composition comprising4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamidemethanesulfonate and an alkaline earth metal carbonate.
 14. Thepharmaceutical composition according to claim 13, further comprising adisintegrating agent.
 15. The pharmaceutical composition according toclaim 13, wherein the alkaline earth metal carbonate is calciumcarbonate.
 16. The pharmaceutical composition according to claim 15,further comprising a disintegrating agent.
 17. The pharmaceuticalcomposition according to claim 13, wherein the alkaline earth metalcarbonate is magnesium carbonate.
 18. The pharmaceutical compositionaccording to claim 17, further comprising a disintegrating agent. 19.The pharmaceutical composition according to claim 14, wherein thedisintegrating agent is at least one agent selected from carmellosesodium, carmellose calcium, carboxymethyl starch sodium, croscarmellosesodium, low-substituted hydroxypropylcellulose and crospovidone.
 20. Thepharmaceutical composition according to claim 13, wherein saidpharmaceutical composition is in a capsule dosage form.
 21. Thepharmaceutical composition according to claim 15, wherein saidpharmaceutical composition is in a capsule dosage form.
 22. Thepharmaceutical composition according to claim 17, wherein saidpharmaceutical composition is in a capsule dosage form.
 23. Apharmaceutical composition comprising:4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamidemethanesulfonate; and means for achieving dissolution of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamidemethanesulfonate.
 24. The pharmaceutical composition according to claim23, wherein said pharmaceutical composition is in a capsule dosage form.25. The pharmaceutical composition according to claim 23, wherein saidpharmaceutical composition is in a tablet dosage form.
 26. Apharmaceutical composition comprising:4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamidemethanesulfonate; and means for achieving dissolution of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamidemethanesulfonate at a dissolution rate that is higher than thedissolution rate of a composition identical to said pharmaceuticalcomposition except lacking said means.
 27. The pharmaceuticalcomposition according to claim 26, wherein said pharmaceuticalcomposition is in a capsule dosage form.
 28. The pharmaceuticalcomposition according to claim 26, wherein said pharmaceuticalcomposition is in a tablet dosage form.